Despite advances in the prophylaxis and acute treatment of cytomegalovirus (CMV), it remains an important pathogen affecting the short- and long-term clinical outcome of solid organ transplant. The emergence of CMV resistance in a patient reduces the clinical efficacy of antiviral therapy, complicates therapeutic and clinical management decisions, and in some cases results in loss of the allograft and/or death of the patient. There is increasing use of antiviral prophylaxis after transplant with little expansion in the range of antiviral agents effective in treatment of CMV. Further understanding is needed of the risk factors for development of CMV antiviral resistance and of therapeutic strategies for treating patients infected with resistant viruses. We review the current status of CMV resistance in solid organ transplant recipients, and provide diagnostic and therapeutic suggestions for the clinician in managing antiviral resistance.